HTLV-1 Tax蛋白和水杨酸类药物调控泛素化的生化机制的研究

发布时间：2018-06-25 10:04

本文选题：HTLV-1 + Tax　；参考：《浙江大学》2016年博士论文

【摘要】：人T细胞白血病病毒Ⅰ(HTLV-1)是第一种被发现的与人类疾病相关的逆转录病毒。它感染着全球超过1500万人,并能够引起包括成年人T细胞白血病(ATL)以及HTLV-1相关性脊髓病/热带痉挛性瘫痪(HAM/TSP)在内的诸多严重疾病。HTLV-1基因组上编码的一个调控蛋白,Tax,能够激活宿主细胞内的IKK-NF-κB信号通路。已有的研究表明,Tax激活IKK-NF-κB通路的能力,对于HTLV-1引起ATL等疾病是必要的。但是,其激活的具体机制并不明了。为了探究Tax激活IKK-NF-κB的具体的生化机制,我们首先建立了一个Tax激活IKK的体外系统。利用这个系统,我们发现泛素转移酶(E2s) UbcH2、UbcH5c和UbcH7对于激活是必要的。在此基础上,我们发现Tax是一个泛素连接酶(E3),它能够利用上述E2合成非锚定的混合型多聚泛素链(free mixed-linkage polyubiquitin chains),而这种泛素链可以直接激活IKK。这项研究揭示了Tax的新型生化功能以及它在激活IKK-NF-κB通路中具体的生化机制,为后续研究以及HTLV-1感染的治疗提供了理论依据。阿司匹林和水杨酸是一类历史悠久运用广泛的消炎止痛药物。一般认为,其作用机制是抑制前列腺素合成酶(COX-1/2),通过减少前列腺素的合成来抑制其引发的炎症反应,但是仍有诸多现象无法以此来解释。在体外反应体系中,我们发现,阿司匹林和水杨酸可以抑制泛素化反应。进一步的研究表明,阿司匹林和水杨酸是一种广谱的泛素转移酶(E2)的抑制剂,可以抑制E2参与的两步泛素化反应,并对所有的检测的E2都有不同程度的抑制能力。在NF-κB炎症信号通路中,阿司匹林和水杨酸可以通过抑制泛素链的合成来抑制下游的转化生长因子-p激活激酶1(TAK1)的激活及后续的κ,B抑制蛋白(Iκ,B)激酶(IKK)的激活,从而阻断信号通路,发挥其抗炎的作用。本研究,揭示了阿司匹林和水杨酸的一种新的作用机制,解释了之前悬而未决的一些疑问,并能够为阿司匹林的临床运用提供依据,为其开拓新的应用领域提供线索。
[Abstract]:Human T cell leukemia virus I (HTLV-1) is the first retrovirus associated with human disease. It affects more than 15 million people around the world, And it can cause many serious diseases, such as adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy / tropical spastic paralysis (HAM / tsp). It can activate the IKK-NF- 魏 B signaling pathway in host cells. Previous studies have shown that the ability of Tax to activate the IKK-NF- 魏 B pathway is necessary for HTLV-1 to induce ATL and other diseases. However, the specific mechanism of its activation is not clear. In order to explore the biochemical mechanism of Tax activating IKK-NF- 魏 B, we first established an in vitro system to activate IKK. Using this system, we found that UbcH2H2UbcH5N1 and UbcH7 are necessary for activation of ubiquitin transferase (E2s). On this basis, we found that tag is a ubiquitin ligase (E3), which can be used to synthesize unanchored mixed polyubiquitin chain (free mixed-linkage polyubiquitin chains), which can directly activate IKK. This study reveals the novel biochemical function of tax and its specific biochemical mechanism in activating IKK-NF- 魏 B pathway, which provides a theoretical basis for further studies and the treatment of HTLV-1 infection. Aspirin and salicylic acid are a class of antiinflammatory and analgesic drugs with a long history. It is generally believed that its mechanism is to inhibit prostaglandin synthase (COX-1 / 2), by reducing the synthesis of prostaglandins to inhibit the inflammatory response, but there are still many phenomena can not be explained. In vitro reaction system, we found that aspirin and salicylic acid can inhibit the ubiquitin reaction. Further studies have shown that aspirin and salicylic acid are an inhibitor of broad-spectrum ubiquitin transferase (E2), which can inhibit the two steps of ubiquitin reaction in which E2 is involved, and have different degrees of inhibition to all the detected E2. In the NF- 魏 B inflammatory signaling pathway, aspirin and salicylic acid block the signal pathway by inhibiting the synthesis of ubiquitin chain to inhibit the downstream activation of transforming growth factor -p-activated kinase 1 (TAK1) and subsequent activation of 魏 B inhibitor protein (I 魏 B) kinase (IKK). Give play to its anti-inflammatory effect. This study reveals a new mechanism of action of aspirin and salicylic acid, explains some outstanding questions before, and can provide evidence for clinical application of aspirin and provide clues for its new application field.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R373

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